Review of Cost-Effectiveness Analysis of Medical Treatment For Myocardial Infarction

Objectives: Myocardial infarction (MI) is a leading cause of death in both the industrialized and developing countries globally. The economic evaluation of MI is undertaken to rationale the alloca-tion of scarce healthcare resource. The objective is to review cost-effectiveness analysis of MI with medications. Methods: We searched PubMed using the key words: “cost effectiveness analysis” and “myocardial infarction”. After applying the selection criteria, eight articles were selected for the present study. Results: Out of eight articles, five had studied thrombolytic agents. All of these papers clearly explain the costs and benefits of different drugs for MI. ICER was assessed in six out of the eight articles to compare the costs and health effects between alternative medications. ICER was expressed in different effect units. Conclusions: This study found that various medications including thrombolytic agents, ACEI and heparin are administered to treat MI in many countries. It is also found that five of eight studies focus on thrombolytic therapies. It implies that thrombolytic is generally very cost effective for MI to the whole society.


INTRODUCTION
Nowadays, myocardial infarction (MI) is one of the major health problems in terms of morbidity and mortality in both developed and developing world. 1 On basis of the redefined definition 2 in 2000, MI is the irreversible necrosis of heart muscle secondary to prolonged ischemia. There are a number of medications and surgical interventions adopted to restore the normal coronary blood flow for patients with MI in the early and post MI treatment. Furthermore, the beneficial efficacy of these therapies has been being observed in different trials in various settings. For instance, the use of aspirin has been shown to reduce Mortality from MI for years, 3 despite the fact that some patients are allergic or resistant to the aspirin; thrombolytic agents such as streptokinase, anistreplase or Anisoylated plasminogen streptokinase activator complex (APSAC), and alteplase (rt-PA) have been proved to be costeffective in many studies [4][5][6][7] since the 1980s; the efficacy of early Lisinopril (angiotensin-convert-ing enzyme inhibitor, ACEI) use in patients with acute myocardial infarction (AMI) 8 was assessed in the GISSI-3 Trail; in the ExTRACT-TIMI25 Trial 9-10 implemented in 48 countries, enoxaparin was found to have better clinical benefits than unfractionated heparin (UFH ) as adjunctive therapy for fibrinolysis in patients with STsegment elevation myocardial infarction (STE-MI. Other important therapies, including beta blockers, 3,11 nitrates, percutaneous coronary intervention (PCI) 3,11 and Coronary artery bypass grafting (CABG), 3 etc. have been proved to have positive effect on the reduction of the mortality rate in MI.
It is known to all, the costs of healthcare/medical interventions are rising enormously worldwide, regardless of the development of modern medical technology. Economic evaluationshave been emerged as important tool to allocate the scarce resources efficiently and rationally. [12][13] Methods of economic evaluations including cost-effectiveness, cost-utility, and cost-benefit analyses are applied to assess health care programs in many arenas containing treatments of MI which impose a high burden on economics worldwide. 14 In relative to various therapies of MI, it is important to measure and compare the different costs, health outcomes and efficacy, then identify the most cost-effective treatment which enables the decision makers to opt from a range of alternatives. It also implies efficient use of health care resources. Like other important health field, MI has also produced economic evaluations in the scientific articles. The aim of this study is to perform a review of the cost-effectiveness analysis of treatments of MI with medications.

METHODS
We searched PubMed with the following search terms: cost effectiveness analysis + myocardial infarction. We found 1099 articles. By limiting the searching terms for randomized clinical trail (RCT), humans and English language we found 133 articles for further review according to the following inclusion and exclusion criteria.

Inclusion criteria
All the selected studies should cover both costs and benefits of drug treatments for MI. Firstly, by reviewing the titles of articles, only those containing terms of "cost-effectiveness" "medications" "myocardial infarction" were retained. Next, studies on the cost-effectiveness of certain pharmaceuticals to treat myocardial infarction were included for the full text review. Finally, if costs and outcome were indicated clearly in the articles, they were included.

Exclusion criteria
Reference studies were excluded if patients of other coronary artery diseases participated in the studies. Studies were excluded if: they were of post-infarction or preventive strategies; they compared medication treatment with surgical treatment.
According to the definition of costeffectiveness analysis, it's not a full economic evaluation when only costs or effects were studied. 14 Therefore we have excluded those studies with only cost or effect.
Reference studies were excluded if found not to be about economic evaluations or costeffectiveness analysis. And studies did not have sufficient details of economic evaluations were excluded as well.

Final selection of the articles
With those criteria we have selected 13 articles after scrutinizing the titles. Then we have read all the 13 abstracts and selected ten articles. After reading the full texts finally eight articles were selected for the current review study.

Criteria for evaluating selected studies
The evaluation criteria of reference studies were based on the check-list developed by Drummond, et al. 14 All the eight articles were then vividly reviewed and evaluated.

RESULTS
Eight articles were finally evaluated in accordance with Drummond's guidelines 14 . All of these papers found explaining the research question and the economic evaluation explicitly. The main and overall results are presented in detail in Table1, and the parameters of costeffectiveness analyses from these articles are discussed in table 2 and 3.
The review highlights that effectiveness of MI treatment depends on some pre-defined conditions (Table 1). Vermer et al 15 indicated that the benefits of thrombolytic treatment were most prominent in patients with anterior infarction as it increases life expectancy. The Swedish study by Levin et al. found that the cost-effectiveness of intravenous thrombolysis treatment in suspected MI is higher than that in other medical therapies of coronary heart disease. 16 Machecourt et al. presented that streptokinase, anistreplase and alteplase are of similar efficacy. 17 Rawles illustrated that the prehospital uitlization of anistreplase could increase the immediate survivals of MI accidents and survivals in longer period of 5 years. 18 Franzosi et al. came to conclusion that isinopril is very beneficial for MI patients with high absolute survival benefit. 19 Lorenzoni et al. stated that selective use of Streptokinase in combination of tPA is more effective than the exclusive use of rt-PA. 20 A recent study from France by Marcoff et al. demonstrated that Women appear to have similar relative and greater absolute risk reductions compared to men when enoxaparin is used with lytic therapy. Total lifetime costs (30-day costs plus the costs beyond trial period) were $1,207 higher in the Enoxaparin group due to the longer life expectancy of patients in Enoxaparin group. 21 An ICER of $4,930 per life years gained was very favorable compared with unfractioned heparin in the base case study from Welsh et al. 22 The papers by Vermeer et al. 15 Franzosi et al. 16 and Levin et al. 17 do not make any compari-sons between different treatments. The study by Vermeer et al. 15 analyzes the cost-benefit of early treatment with intracoronary streptokinase and found streptokinase cost effective in treatment in  17 examines the costs and effects of intravenous thrombolytic therapy of rt-PA and shows it cost-effective in comparison with other coronary heart disease treatments. The studies by Lorenzoni et al. 18 and Machecourt et al. 19 compare the different competing thrombolytic agents. Lorenzoni et al. 18 find that the cost-efficacy of rt-PA and streptokinase differs among countries attributing to the costs difference and prove that the selective use of rt-PA and streptokinase is more cost-effective than the exclusive use of rt-PA. The study by Machecourt et al. 19 demonstrates that there is no significant difference in efficacy between anistreplase, alteplase and streptokinase and the costs of them have little effect on the total cost of MI. The study by Rawles. 20 reveals that prehospital use of Anistreplase increases the survival of patients than the hospital administration of Anistreplase. It shows that prehospital therapy with Anistreplase is highly cost effective compared with streptokinase given in hospital, and the marginal cost-effectiveness ratio is much lower than that for TPA versus streptokinase derived from GUSTO trial. Marcoff et al. 21 explains that Enoxaparin is cost effective when replaced with UFH as adjunctive therapy for fibrinolysis for patients with STEMI in both short-and long-term. Welsh et al. also compares these two drugs, and concludes that Enoxaparin is cost-effective with a modest increase in direct medication costs. 22 Perspectives are not specified in the studies by Vermeer et al., 15 Lorenzoni et al., 18 Rawles, 20 Machecourt et al. 19 and Levin et al. 7 Study by Franzosi et al. 16 applies a perspective of Italian National Health Service while studies from Marcoff et al. 21 and Welsh et al. 22 are of societal perspective. All of these studies state the data sources but the two studies by Rawles 20 and Vermeer et al. 15 ICER is not analyzed in these studies whereas others do ( Table 2).
Levin et al. 7 do not state sensitivity analysis while the rest of studies performed this analysis. In all the studies, costs are interpreted in terms of drug prices, hospitalization, salaries of medical staff, etc. ICER is computed except in the studies by Rawles 20 and Vermeer et al. 15 LYG and QALY is used as outcome measurements by Marcoff et al., 21 Levin et al, 16 and Welsh et al. 22 Quality adjusted mean survival and life expectancy is used to assess health outcome in the study by Vermeer et al. 15 Costs for each extra life saved are used in other cost-effectiveness analyses. Levin et al. 17 and Welsh et al. 22 utilize 5% discount rate and Marcoff et al 21 used 3% discount rate, but costs and effects are not discounted in other studies (Table 3).

DISCUSSION
Among the 8 articles selected, five studies focus on thrombolytic, and the other three studies are about ACEI and heparin. All of these papers are in line with the objectives of this study. Most studies were implemented in developed world and the ExTRACT-TIMI 25 study 10 was conducted in 48 countries, including both developed and developing countries. ICER was assessed in six out of the eight articles to compare the costs  Table 3. Evaluation of the articles according to Drummond's parameters and health effects between alternative medications. ICER was expressed in different effect units.
In the process of literature review, it was found that economic evaluation studies of thrombolytic treatment of MI started from late 1980s 16 and there were more studies on economic evaluations of medication (thrombolytic and other pharmaceuticals) therapy of MI in the 1990s. [16][17][18][19][20] In addition, more studies on surgical treatments in the last decade due to the magnificent achievements in medical technologies. Besides, similar studies tend to be carried out in developing world attributing to a higher prevalence of MI, and the ExTRACT-TIMI25 Trial 9-10 is one example.
It was found that five of the reference studies researched on thrombolytic 15,[16][17][18][19][20] and six studies calculated incremental cost-effectiveness ratio (ICER). Vermeer et al. 15 only studied the costs and outcome for the cost-benefit analysis of streptokinase and Rawles 18 utilized marginal analysis to measure the cost-effectiveness of Anistreplase. Among the other three thrombolytic studies, ICERs were evaluated. Lorezoni et al. 20 reported the values of ICERS of rt-PA and streptokinase which vary greatly among four countries because of difference in the costs of drugs; and the site-selective use of both rt-PA and streptokinase halves the cost-effectiveness ratio compared to the exclusive use of rt-PA for AMI. Machecourt et al., 17 proved that there is no significant difference between anistreplase, alteplase and streptokinase in cost/efficacy ratio, and this finding is different from a previous study 23 as the previous research did not incorporate costs in the hospital phase. Machecourt et al 17 also illustrated that streptokinase is consistently of slight advantage when compared with the other two thrombolytic agents. Levin et al. 16 concluded that intravenous rt-PA is costeffective by comparing the ICER with that of other treatments of coronary heart diseases, taking the study by Vermeer et al. 15 for example. The comparison in the former study was made among three thrombolytic agents, whereas the latter study compared intracoronary streptokinase with beta adrenergic antagonists and coronary artery bypass surgery. The difference between the studies by Machecourt et al. 19  In studies regarding ACEI 19 and enoxaparin and UFH 21,22 , all of them included ICERs. Franzosi et al. 19 found that the ICER of lisinopril is lower compared with that of other therapies for AMI, given similar benefit and routinely utilization. E.g. the ICER of lisinopril was $US 2080 per life year saved compared with $US 32687 per life year saved of alteplase (rt-PA) which was found to be more cost-effective in the study by Levin et al. 16 However, deviation might occur when comparing different cost-effectiveness analyses in different settings, due to a difference in health care systems, drug prices, cultures, etc. On the contrary, when it comes to enoxaparin and UFH, both Marcoff et al. 21 and Welsh et al. 22 reached the same conclusion that using enoxaparin instead of UFH in conjunction with fibrinolysis in STEMI patients is cost effective by evaluating the ICERs, and the results were found to be in line with other studies. 24,25 All the studies that we analyzed, excluding the multiple-country trial ExTRACT-TIMI 25, 10 reported achievements in many developed countries in the research of the health care expenditures, health outcome and effects of various health programs for treatments of MI. However, very few researches were done in the less developed countries and it is very difficult for patients with MI to get access to the medical service. The inequality is assumed to be resulted from inappropriate distribution of healthcare resources, lower income, high costs of treatments for MI, underdevelopment in transportation in developing world.
The present study also found that treatment strategies such as PCI, stenting angioplasty, CABG are more commonly used in recent decades than that in the past. Meanwhile, medications still play an important role. For instance, two American specialists of cardiology points out that if PCI capability is not available or will cause a delay over 90minutes, then the optimal approach is to administer thrombolytics within 12 hours of onset of symptoms in patients with ST-segment elevation greater than 0.1 mV or more continuous ECG leads, new left bundlebranch block or anterior ST-depression consistent with posterior infarction. 26 Streptokinase, APSAC or anistreplase and rt-PA, which are commonly used, are found to have no significant difference in efficacy rates with respect to hospital mortality and imminent risk of massive haemorrhage. 7 The benefit of thrombolytic agents is dependent on the early administration of the drug, and Rawles 20 illustrated the timely implementation of anistreplase. Despite the substantial overall benefits of the medical approaches, adverse effects and limitations of the pharmaceuticals must be taken into account. E.g. antitrombotic agent enoxaparin has been found to lead to an increase in major bleeding in patients with STEMI; 27 rt-PA show a significant efficacy in patients younger than 75 years and in patients with anterior acute myocardial infarction, but no evident advantage in those over 75 and with non-anterior acute myocardial infarction. 28 Hence, to make most of the medications of MI, subgroup analysis is required.
Myocardial infarction is a major cause of morbidity and mortality throughout the world. MI treatment is one of the most expensive interventions for acute coronary syndromes, exerting a detrimental influence on the economic growth and well being. The burden of disease falls both in developed and developing countries. Thus, it is of great importance to gain deeper insights to MI, and seek for appropriate treatments which are cost effective to the whole population.
Economic evaluation of MI treatments provides a great deal of information to decision makers to identify and opt between different regimens. It is vital to state the perspective of a study, as a program appears unattractive and costly from one viewpoint may be considered effectively applicable from other viewpoints 14 . Yet, they were not specified in most of the studies above. None of these studies except the one by Rawles 20 did marginal analysis and Levin et al. 17 did not perform sensitivity analysis, though both analyses are important in economic evaluations. ICER, which is crucial in economic analysis, is reported explicitly in all the studies but the ones by Vermeer et al. 15 and Rawles. 20 It is recommended that future cost-effectiveness studies should include all the important aspects of an economic evaluation in particular ICER.
This study found that in many countries various medications including thrombolytic agents, ACEI and heparin are cost-effective when administered for MI treatment. It is also found that five of eight studies focus on thrombolytic therapies. The prompt delivery of thrombolytic therapy increases the efficacy which will result in a decrement on the costs of further treatment. To sum up, it implies that thrombolytic is very cost effective for MI in a range of countries with different settings.
It is also suggested that similar studies be undertaken in developing countries where there is a high burden of disease but lack of relevant interventions and studies.